Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCCC>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:10])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.8 %

Procedure:
To a cooled (0° C.) solution of (S)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate (6.35 g, 22.7 mmol) in THF (114 mL) was added a solution of LAH in THF (2.0 M, 13.64 mL, 27.3 mmol) and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was quenched by addition of a 1N NaOH solution until gas evolution ceased. The reaction mixture was filtered, washed with EtOAc. After separation, the aqueous phase was washed with EtOAc (2×150 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 100%) provided (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate as a white solid (5.01 g, 84% yield).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][CH2:12][CH2:11][C:10]2([CH3:16])[CH3:15])[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[OH:17][C:18]1[CH:27]=[C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:14]=2[O:13][CH2:12][CH2:11][C:10]3([CH3:16])[CH3:15])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: C#CC(O)c1cccc2c1OCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(O)c2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.00 g (13.9 mmol) of α-ethynyl-4,4-dimethylchroman-8-methanol, 3.90 g (13.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 100 ml of triethylamine are introduced into a three-necked flask. The reaction mixture is degassed with nitrogen for 30 minutes and then 780 mg (1.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 320 mg (1.7 mmol) of copper iodide are successively added. The reaction mixture is stirred at room temperature for 4 hours and is evaporated to dryness and the residue obtained is taken up in water and ethyl ether. The organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 50% ethyl acetate and 50% heptane. 2.85 g (56%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate are collected in the form of a white solid with a melting point of 122-123° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC#N.O>[NH2:1][C:2]1[C:3]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1sc2ccc(Br)cc2c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2ccc(-c3ccccc3)cc2c1N
Temperature: 80 °C
Yield: 8.4 %

Procedure:
To a stirred solution of 3-amino-5-bromo-benzo[b]thiophene-2-carboxylic acid amide (90 mg, 0.33 mmol) in DMF (5 mL) was added phenylboronic acid (1.2 eq., 50 mg) at room temperature, under nitrogen. The resulting mixture was degassed and placed under nitrogen after which time sodium carbonate (1.2 eq., 43 mg) and Pd(Ph3)4 (0.4 eq., 155 mg) were added. The reaction was degassed again and warmed to 80° C. overnight, under nitrogen. Upon cooling to room temperature, the reaction was concentrated to dryness and the remaining residue was purified via flash column chromatrography (5 g SiO2, 0-40% EtOAc/dichloromethane). The product-containing fractions were concentrated to give the product which was still contaminated. The brown solid was diluted with 1:1 CH3CN/H2O and the remaining solids were removed via filtration. The filtrate was re-purified using preparatory reverse phase HPLC to give 7.4 mg (8%) of the title compound as a white solid.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[CH2:41]([O:48][CH2:49][CH2:50][CH2:51]O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[ClH:19].[CH2:41]([O:48][CH2:49][CH2:50][CH2:51][O:37][C:31]1[CH:30]=[C:29]2[C:34]([C:25]([NH:24][C:23]3[CH:38]=[CH:39][C:20]([Cl:19])=[CH:21][C:22]=3[F:40])=[N:26][CH:27]=[N:28]2)=[CH:33][C:32]=1[O:35][CH3:36])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OCCCOCc1ccccc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOCc1ccccc1
Product: Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
1,1′-(azodicarbonyl)dipiperidine (480 mg, 1.9 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.63 mmol), 3-benzyloxypropanol (150 μl, 0.95 mmol) and tributylphosphine (459 μl, 1.86 mmol) in methylene chloride (20 ml) at 5° C. The reaction was stirred for 1 hour at 5° C. and then for 18 hours at ambient temperature. The mixture was diluted with ether and stirred for 15 minutes. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was partitioned between ethyl acetate and water, and the organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. A 1M solution of ethereal hydrogen chloride was added to the residue, the resulting solution was reduced in volume by evaporation and the resulting precipitate was collected by filtration and dried to give 7-(3-benzyloxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (90 mg, 31%).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:23]=[C:21]1[CH2:20][C:7]2[C:6](=[C:11]([S:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Sc2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cccc(Sc3ccc(Cl)cc3)c2N1
Yield: 88 %

Procedure:
A mixture of iron powder (21.6 g) and ammonium chloride (2.2 g) in ethanol (200 ml) and water (75 ml) and ethyl 2-[2-nitro-3-(4-chlorophenylthio)phenyl]acetate (21.6 g) were treated in a similar manner to that of Preparation 28-(1) to give 2-oxo-7-(4-chlorophenylthio)indoline (14.9 g). mp 186°-188° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[N:7]#[C:8][Br:9]>>[BrH:9].[CH3:4][C:3]1([CH3:5])[CH2:2][NH:1][C:8](=[NH:7])[NH:6]1
Reactant: CC(C)(N)CN
Reactant: N#CBr
Product: Br
Product: CC1(C)CNC(=N)N1
Yield: 99.5 %

Procedure:
The process is carried out according to the procedure described in stage f of Example 1, using 21 g of 1,2-diamino-2-methylpropane and 25.3 g of cyanogen bromide. 46 g of 4,4-dimethylimidazolidin-2-ylideneamine hydrobromide are thus obtained, in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]=[CH:13][CH2:12][CH2:11]2.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([O:18][CH3:19])[C:8]([O:7][CH3:6])=[CH:9][C:10]=2[CH:11]=1)([O-:29])=[O:28]
Reactant: COc1cc2c(cc1OC)CCC=C2
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)CCC(c1ccccc1[N+](=O)[O-])=C2
Temperature: 140 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
Pd(PPh3)2Cl2 (840 mg, 1.2 mmol) and sodium acetate (200 mg, 2.4 mmol) were added to a solution of 6,7-dimethoxy-3,4-dihydronaphthalene (2, 700 mg, 3.7 mmol) and 1-iodo-2-nitrobenzene (925 mg, 3.7 mmol) in dimethylacetamide (50 mL). The mixture was stirred under nitrogen at 140° C. overnight, and then concentrated in vacuo. Ethyl acetate (60 mL) was added to the residue and washed with distilled water (50 mL). The organic layer was separated and passed through a celite bed. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed to give compound 3 (330 mg) in 29% yield; 1H NMR (CDCl3) d 2.51(2H, t, J=8.1), 2.92(2H, t, J=8.1), 3.87(3H, s), 3.90(3H, s), 6.45(1H, s), 6.67(1H, s), 6.73(1H, s), 7.38˜7.45 (2H, m), 7.54˜7.62(1H, m), 7.88˜7.93(1H, m); 13C NMR d 28.5, 28.5, 56.6, 111.0, 111.7, 124.9, 127.0, 127.1, 128.1, 128:3, 131.3, 133.3, 135.7, 138.7, 147.9, 148.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:12]([CH3:24])=[N:11][C:10]=1[CH2:25][CH2:26][CH3:27].BrB(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]([CH3:24])=[N:11][C:10]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 3′-fluoro-4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.35 g) in methylene chloride (10 mL) was added tribromoborane (1.0 M methylene chloride solution, 20 mL) at room temperature. After being stirred at room temperature for 12 hr, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a white solid (2.25 g, 99%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:19])[CH2:14][CH2:15][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Methanesulfonyl chloride (21.91 g, 14.81 mL, 191.30 mmol) is added slowly (10 min) to a solution of 4-(4-bromophenyl)-4-piperidinol (50.00 g, 191.30 mmol) and triethylamine (29.04 g, 40.00 mL, 286.95 mmol) in tetrahydrofuran (575 mL) at 23° C. (internal temperature) under nitrogen atmosphere. The mixture is stirred at 23° C. for 30 min. 500 mL of 1 M aq hydrochloric acid are added and the mixture is stirred for 10 min. The mixture is extracted with ethyl acetate (2×500 mL) the organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is removed to obtain 60.0 g of the title compound as a white solid. MS m/e (79Br/81Br) 333, 335 (M+1).
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O.O>[N:13](=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)[OH:14]
Reactant: NO
Reactant: O=C1CCCc2cccnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2cccnc21
Yield: 79.7 %

Procedure:
A solution of 2.22 g of 8-oxo-5,6,7,8-tetrahydroquinoline, 2.1 g of hydroxylamine hydrochloride, and 4.1 g of sodium acetate in 15 mL of 3:1 ethanol-water was heated at 70° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. Evaporation of the extracts gave 1.95 g of product which was pure enough by NMR to be used in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[C:8]3[S:14][CH2:13][CH:12]([CH3:15])[N:9]32)=[CH:4][C:3]=1[F:20].[CH:21]1([NH:24][CH2:25][CH:26]2[CH2:30][CH2:29]NC2)[CH2:23][CH2:22]1.[N:31]1C=CC=C[CH:32]=1>>[F:20][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:31]1[CH2:32][CH2:29][CH2:30][CH:26]1[CH2:25][NH:24][CH:21]1[CH2:22][CH2:23]1)[N:9]1[CH:12]([CH3:15])[CH2:13][S:14][C:8]1=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19]
Reactant: C1CC(CNC2CC2)CN1
Reactant: c1ccncc1
Reactant: CC1CSc2c(C(=O)O)c(=O)c3cc(F)c(Cl)cc3n21
Product: CC1CSc2c(C(=O)O)c(=O)c3cc(F)c(N4CCCC4CNC4CC4)cc3n21

Procedure:
A mixture of 3.14 g (10 mmol) of 8-chloro-7-fluoro-1-methyl-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid, 2.1 g (15 mmol) of N-cyclopropyl-3-pyrrolidinemethanamine and 50 ml of pyridine is heated at reflux for 24 hours. The solvent is removed in vacuo and the residue triturated with water. The solid which forms is removed by filtration, washed with water, and dried in vacuo to give 7-fluoro-1-methyl-8-[[3-cyclopropylamino)methyl-1-pyrrolidinyl]-5-oxo-1,2-dihydro-5H-thiazolo-[3,2-a]quinoline-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([NH:14][CH3:15])[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[N:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.[Br:40]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Br:40][C:8]1[C:9]([NH:14][CH3:15])=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([O:4][C:3]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:2]=2[F:1])=[C:6]([C:16]2[C:17]3[CH:26]=[N:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1c(Br)cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 4-[2-(2,4-difluorophenoxy)-4-(methylamino)-3-nitrophenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.433 g, 0.776 mmol) in N,N-dimethylformamide (5.0 mL) was cooled to 0° C. Two portions of N-bromosuccinimide (0.159 g, 0.893 mmol) were added with a 5 min interval to the above solution at 0° C., and the resultant reaction mixture was stirred at 0° C. for 30 min, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with saturated sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes [EtOAc contained 5% MeOH]) gave the desired product (444 mg, 90%) as a yellow solid. LCMS calculated for C26H29BrF2N5O5Si (M+H)+: m/z=636.1, 638.1. found: 636.0, 638.1.
Reaction SMILES: C(OCCCC)(=O)C=C.[C:10]([O:15][CH3:16])(=O)[C:11](C)=C.[C:17]([O:21][CH2:22][CH2:23][OH:24])(=O)C=C.C(O)(=O)C=C.C(OOC(C)(C)C)(C)(C)C>C(OCCO)CCC>[CH2:10]([O:15][CH2:16][CH2:17][O:21][CH2:22][CH2:23][OH:24])[CH3:11]
Reactant: C=CC(=O)OCCO
Reactant: C=C(C)C(=O)OC
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCCC
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CCCCOCCO
Product: CCOCCOCCO
Yield: 5.8 %

Procedure:
70 g of ethylene glycol monobutyl ether, 70 g of diethylene glycol monoethyl ether and 150 g of the polyether A1) described in example 2 were weighed into a 4 liter reaction vessel equipped with stirring, cooling and heating devices and heated to 155° C. A mixture of 360 g of butyl acrylate, 420 g of methyl methacrylate and 75 g of hydroxyethyl acrylate was then added over a period of 2 hours, while simultaneously adding 25.7 g of di-tert.-butyl peroxide dissolved in 8 g of ethylene glycol monobutyl ether and 8 g of diethylene glycol monoethyl ether to form copolymer A2). Immediately thereafter, a mixture of 139 g of butyl acrylate, 195 g of methyl methacrylate, 82 g of hydroxyethyl acrylate and 34 g of acrylic acid was added over a period of 1 hour, while simultaneously adding 19.3 g of di-tert.-butyl peroxide dissolved in 5.5 g of ethylene glycol monobutyl ether and 5.5 g of diethylene glycol monoethyl ether over a period of 1.5 hours to form copolymer A3). After stirring for a further 2 hours at 150° to 155° C., the temperature was reduced to 100° C., 52.5 g of dimethylethanolamine were added and the mixture dispersed in 1670 g of distilled water. The resulting aqueous binder dispersion A) had a solids content of 44%, an organic solvent content of 4.8%, an acid number of 21 and an OH number of 106.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[C:29](OCC)(OCC)[CH2:30][CH2:31][CH2:32][CH3:33])C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(OCC)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concetrated to give a green oil. The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 4.12 g of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:55][N:56]([CH3:61])[CH2:57][C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][CH2:30][N:31]([C:58](=[O:59])[CH2:57][N:56]([CH3:61])[CH3:55])[CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCNCCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(Z)-azanediylbis(propane-3,1-diyl) dioleate TFA salt (750 mg, 1.13 mmol) was diluted with DCM (5 mL) and added to a pre-activated mixture of N,N-dimethylglycine (128 mg, 1.24 mmol), HATU (517 mg, 1.36 mmol) and DIEA (413 uL, 2.37 mmol) in DCM (5 mL). Flask was flushed with argon and allowed to stir at room temperature overnight. The reaction mixture was concentrated, and subjected to silica gel chromatography with a DCM/MeOH gradient to yield (Z)-((2-(dimethylamino)acetyl)azanediyl)bis(propane-3,1-diyl) dioleate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:17]=[CH:18][CH:19]=3)[N:11]=[C:12]([CH3:16])[C:13]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:17]=[CH:18][CH:19]=3)[N:11]=[C:12]([CH3:16])[C:13]=2[CH:14]=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1nn2cccc2c(-c2ccc(F)cc2)c1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn2cccc2c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol (505 mg) and triethylamine (997 mg) in dichloromethane (4 mL) and dimethyl sulfoxide (2 mL) was added sulfur trioxide pyridine complex (941 mg) in an ice-water bath under nitrogen. After 30 minutes, the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to about ⅓ volume. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 30 mL) eluted with hexane-chloroform=3-1 and 2-1 to give 4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde as an yellow solid (340 mg, 67.9%).